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TitleCryo-EM structure of the full-length LGR4-RSPOs complex and a targeting nanobody for anti-obesity therapy.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 8406, Year 2025
Publish dateSep 25, 2025
AuthorsZhongyun Zhang / Lu Wang / Huarui Qiao / Haowen Jiang / Shaojue Guo / Yuying Li / Ningning Zhang / Tengjie Geng / Qianqian Cui / Zhongyun Lan / Jie Hong / Weiqiong Gu / Ruixin Liu / Guang Ning / Jia Li / Jiqiu Wang / Yong Geng /
PubMed AbstractObesity poses a substantial threat to human health but lacks effective management. Recent advancements in large-scale deep sequencing and cryo-electron microscopy (cryo-EM) have transformed drug ...Obesity poses a substantial threat to human health but lacks effective management. Recent advancements in large-scale deep sequencing and cryo-electron microscopy (cryo-EM) have transformed drug discovery paradigms. Leveraging prior genetics investigation, we pinpointed Leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) as a promising target for combating obesity. Here, we present cryo-EM structures of full-length LGR4 alone and in complex with RSPO2(FU). Notably, we develop an inhibitory nanobody (NB21) that blocks the binding of RSPO1/2 to LGR4, and we also determine the structure of the LGR4-NB21 complex. NB21-mFc (NB21 fused with mouse IgG2) effectively inhibits the canonical Wnt signaling pathway, thereby enhancing mitochondrial respiration and thermogenesis in beige adipocytes. In vivo, NB21-mFc increases energy expenditure by promoting the browning of white fat, conferring resistance to both diet-induced and genetic (ob/ob) obesity. Furthermore, LGR4 deficiency abolishes the effects of NB21-mFc in boosting the browning program and subsequent weight reduction. In summary, our study unveils structural insights into the LGR4-RSPOs and LGR4-NB21 complexes, paving the way for the development of an LGR4-targeting nanobody for weight loss.
External linksNat Commun / PubMed:40998774 / PubMed Central
MethodsEM (single particle)
Resolution2.9 - 3.1 Å
Structure data

38641

8xt9

EMDB-38641, PDB-8xt9:
structure of LGR4
Method: EM (single particle) / Resolution: 3.1 Å

38677

8xum

EMDB-38677, PDB-8xum:
Structure of LGR4 with RSPO2
Method: EM (single particle) / Resolution: 2.9 Å

Source
  • homo sapiens (human)
  • camelus bactrianus (Bactrian camel)
KeywordsMEMBRANE PROTEIN / LGR4 / RSPO2

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